The present invention relates to interleukin (IL) antagonists for the treatment of neurological disorders, trauma, injuries or compression; neurodegenerative disorders including Alzheimer""s Disease; demyelinating neurological disorders including multiple sclerosis; retinal disorders; and muscular disorders. More particularly, the IL antagonists are used in a new treatment of these disorders by inhibiting the action of IL in the human body. The administration of these IL antagonists is performed by intrathecal administration; intracerebroventricular administration; intranasal administration; by inhalation; or by alternative routes of administration.
Neurological disorders due to demyelinating disease (e.g. multiple sclerosis), immune disease, inflammation, trauma, or compression, occur in different clinical forms depending upon the anatomic site and the cause and natural history of the physiological problem. Common to all of these disorders is the fact that they can cause permanent neurological damage, that damage can occur rapidly and be irreversible, and that current treatment of these conditions is unsatisfactory, often requiring surgery and/or the use of pharmacologic agents, which are often not completely successful.
These neurological conditions include acute spinal cord trauma, spinal cord compression, spinal cord hematoma, cord contusion (these cases are usually traumatic, such as motorcycle accidents or sports injuries); nerve compression, the most common condition being a herniated disc causing sciatic nerve compression, neuropathy, and pain; but also including cervical disc herniation, causing nerve compression in the neck; acute or chronic spinal cord compression from cancer (this is usually due to metastases to the spine, such as from prostate, breast or lung cancer); autoimmune disease of the nervous system; and demyelinating diseases, the most common condition being multiple sclerosis. Tissues related to the neurological system, those being the retina, optic nerve, and muscle, can be similarly affected.
Steroid drugs, such as cortisone, that are used to treat the aforementioned neurological problems and conditions are particularly hazardous because they are used either at high dosage, with a corresponding increasing risk of side effects, or because they are used chronically, also increasing their adverse effects. Lastly, steroids are only partially effective or completely ineffective.
Members of the interleukin family, including interleukin 1(IL-1), have been demonstrated to be key components of inflammation of the central nervous system and the retina. Antagonists of these cytokines which are in development include interleukin 1 receptor antagonist (IL-1 RA) and interleukin 1 receptor type II (IL-1R type II). Other interleukin antagonists which are the subject of this patent include the following: monoclonal antibodies to interleukin 1 (including both chimeric and fully humanized forms); soluble receptors to interleukin 1; soluble receptors to interleukin 1 fused to an Fc Immunoglobulin fragment (a fusion protein, similar to etanercept except substituting IL-1 for TNF). Use of these interleukin antagonists can suppress this inflammation, which is important to the pathogenesis of a variety of clinical disorders. These disorders include uveoretinitis and the neurodegenerative diseases, including Alzheimer""s Disease and Parkinson""s Disease.
Clinical development of the interleukin antagonists has been confined to use for arthritis. For this use, peripheral administration is effective. The blood-brain barrier, however, interferes with the penetration of peripherally administered interleukin antagonists. Therefore, the use of these agents by intravenous, subcutaneous, intramuscular, or other peripheral routes will be less effective for the treatment of disorders of the central nervous system (including the brain and spinal cord) or the retina.
The inventor has received U.S. Pat. No. 6,015,557 for the use of TNF antagonists for the treatment of neurological disorders. Included in this patent is the intrathecal use of TNF antagonists. The present patent introduces the novel concept of the intrathecal administration of interleukin antagonists. Intrathecal administration (administration directly into the cerebrospinal fluid), either at the level of the spinal cord, or directly into the cerebroventricular system, allows these antagonists to reach the brain, spinal cord, or retina in therapeutically effective amounts. Peripheral administration of these agents for these uses may be less effective. These uses will ameliorate inflammation, and will therapeutically improve a variety of disorders with inflammatory or autoimmune components.
Acute and/or chronic intrathecal therapy with interleukin antagonists is thereby presented as a treatment for a diverse variety of acute and chronic neurological, retinal and muscular disorders, including:
Alzheimer""s Disease
Parkinson""s Disease
Pick""s Disease
Huntington""s Disease
Neurodegenerative Diseases
AIDS Dementia Complex
Inflammatory Diseases of the Brain, Spinal Cord, or Retina
Autoimmune Diseases of the Brain, Spinal Cord, or Retina
Multiple Sclerosis
Spinal Cord Injury
Spinal Cord Compression
Herniated Disc
Traumatic Brain Injury
Muscular Dystrophy
Polymyositisxe2x80x94Dermatomyositis
There remains a need for a new pharmacologic treatment of these aforementioned physiological problems of the nervous system, retina, and muscle, associated with inflammation, autoimmune disease, demyelinating diseases, trauma, injuries and compression. The pharmacological use of IL antagonists are greatly beneficial for the large number of patients whom these conditions affect. IL antagonists may be used for the immediate, short term and long term (acute and chronic) blockade of IL in order to minimize neurologic damage mediated by IL dependent processes occurring in the aforementioned neurological disorders. The use of these IL antagonists will result in the amelioration of these physiological neurological, retinal and muscular disorders. Intrathecal administration of the IL antagonists is the preferred treatment for disorders of the central nervous system, including Alzheimer""s disease and other neurodegenerative diseases; and for disorders of the optic nerve and the retina.
Pharmacologic chemical substances, compounds and agents which are used for the treatment of neurological disorders, trauma, injuries and compression having various organic structures and metabolic functions have been disclosed in the prior art. For example, U.S. Pat. Nos. 5,756,482 and 5,574,022 to ROBERTS et al disclose methods of attenuating physical damage to the nervous system and to the spinal cord after injury using steroid hormones or steroid precursors such as pregnenolone, and pregnenolone sulfate in conjunction with a non-steroidal anti-inflammatory substance such as indomethacin. These prior art patents do not teach the use of IL-1 antagonists or IL-1 blocker for the suppression and inhibition of the action of IL-1 in the human body to treat neurological disease, trauma, injury or compression, or autoimmune neurologic disease as in the present invention.
U.S. Pat No. 5,650,396 discloses a method of treating multiple sclerosis (MS) by blocking and inhibiting the action of TNF in a patient. This prior art patent does not teach the use of the IL-1 antagonists as in the present invention.
U.S. Pat. No. 5,863,769 discloses using IL-1 RA for treating various diseases. However, it does not disclose administering IL Blockers intrathecally into the cerebrospinal fluid (CSF), as in the present invention.
U.S. Pat. No. 6,013,253 discloses using interferon and IL-1 RA for treating multiple sclerosis. However, it does not disclose administering IL Blockers intrathecally into the cerebrospinal fluid (CSF) for treating Alzheimer""s and related diseases.
U.S. Pat. No. 5,075,222 discloses the use of IL-1 inhibitors for treatment for various disorders. However, it does not disclose administering IL Blockers intrathecally into the CSF for treating Alzheimer""s and related diseases.
None of the prior art patents disclose or teach the use of intrathecal administration of IL antagonists as in the present invention for suppression and inhibition of the action of IL in a human to treat neurological disease, trauma, injury or compression, or demyelinating neurologic disease, in which the IL antagonist provides the patient with a better opportunity to heal, slows disease progression, prevents neurological damage, or otherwise improves the patient""s health.
Accordingly, it is an object of the present invention to provide IL antagonists as a new pharmacologic treatment of neurological disorders, trauma, injuries and compression affecting the nervous system of the human body; demyelinating neurologic disease; neurodegenerative diseases; retinal diseases; and muscular diseases; such that the use of these IL antagonists will result in the amelioration of these conditions.
Another object of the present invention is to provide IL antagonists for providing suppression and inhibition of the action of IL in a human to treat neurological injury, trauma or compression; demyelinating neurologic disease; neurodegenerative diseases; retinal diseases; and muscular diseases.
Another object of the present invention is to provide IL antagonists that reduce inflammation by inhibiting the action of IL in the human body for the immediate, short term (acute conditions) and long term (chronic conditions), such that this reduction in inflammation will produce clinical improvement in the patient and will give the patient a better opportunity to heal, slow disease progression, prevent neurological damage, prevent retinal and muscular damage, or otherwise improves the patient""s health.
Another object of the present invention is to provide IL antagonists, using intrathecal administration as the preferred form of administration, that offer acute and chronic treatment regimens for neurological conditions caused by neurological trauma, compression, injury and/or disease, such conditions including acute spinal cord injury, herniated nucleus pulposus (herniated disc), spinal cord compression due to metastatic cancer, primary or metastatic brain tumors, chronic pain syndromes due to metastatic tumor, increased intracranial pressure, demyelinating diseases such as multiple sclerosis, inflammatory CNS diseases, such as subacute sclerosing panencephalitis, other related neurological disorders and diseases, retinal disorders, and muscular disorders.
The present invention provides a method for inhibiting the action of IL for treating neurological, retinal, and muscular disorders in a human by administering to the human therapeutically effective doses of IL antagonists for reducing the inflammation of neuronal, retinal, or muscular tissue of the human and/or preventing immune system damage to neuronal, retinal, or muscular tissue. The preferred forms of administration are intrathecal and intracerebroventricular administration into the cerebrospinal fluid (CSF).